Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new accolate research articles will be listed here shortly after becoming available to us.
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Medical research on accolate
Tolerance and rebound with zafirlukast in patients with persistent asthma.
J Negat Results Biomed. 2008; 7: 3
Reid DW, Misso NL, Aggarwal S, Thompson PJ, Johns DP, Walters EH
BACKGROUND: The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined. OBJECTIVE: To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD20FEV1), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E2 and exhaled nitric oxide (eNO) levels. METHODS: A double blind, placebo-controlled study of zafirlukast, 20 mg twice daily over 12 weeks in 21 asthmatics taking beta2-agonists only (Group I), and 24 subjects treated with ICS (Group II). RESULTS: In Group I, zafirlukast significantly improved morning PEF and FEV1compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV1 improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, beta2-agonist use and asthma severity scores (p < 0.05). However, most improvements with zafirlukast in Group I and to a lesser extent in Group II deteriorated toward baseline values over 12 weeks. In both groups, one week following zafirlukast withdrawal there were significant deteriorations in morning and evening PEFs and FEV1 compared with placebo (p < or = 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD20FEV1, sputum CysLT concentrations or exhaled nitric oxide (eNO) levels. However, blood neutrophils significantly increased in both groups following zafirlukast withdrawal compared to placebo (p = 0.007). CONCLUSION: Tolerance appears to develop to zafirlukast and there is rebound clinical deterioration on drug withdrawal, accompanied by a blood neutrophilia.
Reduction of Capsular Thickness around Silicone Breast Implants by Zafirlukast in Rats.
Eur Surg Res. 2008 Mar 27; 41(1): 8-14
Spano A, Palmieri B, Palmizi Taidelli T, Nava MB
Capsular contracture is a very disappointing complication, with an overall incidence between 0.5 and 30% of breast implant operations and, if severe, requiring a further surgical procedure (capsulotomy or capsulectomy). Many frustrating attempts have been made to prevent the fibrotic reaction, mainly with steroids or antibiotics. More recently leukotriene antagonists clinically used in the asthma and lung diseases have been suggested to be potentially useful in counteracting the inflammatory pathway leading to a dense collagen membrane around the prosthesis and thus preventing contracture of the capsule. In this study we evaluated the effectiveness of zafirlukast with the following protocol. Disks of textured implant material were placed dorsally into each of the subcutaneous tissues of 40 rats that were subdivided in 2 groups: 20 rats treated with zafirlukast and 20 controls. At autopsy 77 days after, each implant with its surrounding collagenic tissue was excised, and the macroscopic measure of the membrane thickness was compared with the pathology reports, to definitely assess the foreign body reaction. The mean total thickness of the capsule around the implants was 161.97 mum in the zafirlukast-treated group compared with 345.98 mum in the control group (p < 0.001). Outstandingly, the collagen fibers and fibroblast layer were reduced in the zafirlukast-treated group compared to the controls. Our study confirms the effectiveness of this compound in preventing fibrosis and putatively also in reducing the extent of collagen reaction when a capsule has been formed. Copyright (c) 2008 S. Karger AG, Basel.
Pharmacological intervention to the inflammatory response from decompression sickness in rats.
Aviat Space Environ Med. 2008 Feb; 79(2): 87-93
Little T, Butler BD
INTRODUCTION: Venous bubbles resulting from experimental decompression sickness (DCS) may cause an inflammatory-like reaction with activation of granulocytes and release of metabolites from arachidonic acid. The release of cyclooxygenase and lipoxygenase pathway mediated metabolites, namely thromboxane B2 (TXB2) and leukotriene E4 (LTE4) likely contribute to this overall DCS response. In the present study we examined the effect on DCS outcome of several agents affecting both pathways. METHODS: Indomethacin and acetylsalicylic acid were administered to study the cyclooxygenase pathway mediators, Zafirlukast and Zileuton to study inhibition of the lipoxygenase pathway, and isoproterenol for its beta-agonist effects. The agents were administered to randomly selected Sprague-Dawley rats prior to compression to 683 kPa for 60 min. Following 60 min recovery post-decompression, DCS evaluation included: gross symptoms; pulmonary edema; bronchoalveolar lavage and pleural fluid protein; white blood cell and differential cell counts; and urine, bronchoalveolar lavage, and plasma TXB2 and LTE4 analysis. RESULTS: The results indicate that both Zafirlukast and Zileuton reduced the reported DCS symptoms, pulmonary edema, pleural and bronchoalveolar lavage protein levels, white blood cell counts in the pleural and bronchoalveolar lavage, and leukotriene levels in the bronchoalveolar lavage vs. that of vehicle-treated rats exposed to compression/decompression. The effect of these agents on pleural and bronchial alveolar protein levels demonstrated protective effects on microvascular permeability. Acetylsalicylic acid and indomethacin treatment had less effect on reducing inflammatory-induced changes. DISCUSSION: The effect of inflammatory-like responses to DCS can be altered with pharmacological intervention given prior to compression.
Biomed Chromatogr. 2008 Jun; 22(6): 645-53
Bharathi DV, Naidu A, Jagadeesh B, Laxmi KN, Laxmi PR, Reddy PR, Mullangi R
A highly sensitive and specific LC-MS/MS method has been developed and validated for the estimation of zafirlukast (ZFK) with 500 microL human plasma using valdecoxib as an internal standard (IS). The API-4000 LC-MS/MS was operated under multiple reaction-monitoring mode using the electrospray ionization technique. The assay procedure involved extraction of ZFK and IS from human plasma with ethyl acetate. The resolution of peaks was achieved with 10 mm ammonium acetate (pH 6.4):acetonitrile (20:80, v/v) on a Hypersil BDS C(18) column. The total chromatographic run time was 2.0 min and the elution of ZFK and IS occurred at approximately 1.11 and 1.58 min, respectively. The MS/MS ion transitions monitored were 574.2 --> 462.1 for ZFK and 313.3 --> 118.1 for IS. The method was proved to be accurate and precise at a linearity range of 0.15-600 ng/mL with a correlation coefficient (r) of >/=0.999. The method was rugged with 0.15 ng/mL as lower limit of quantitation. The intra- and inter-day precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a pharmacokinetic study in human volunteers following oral administration of 20 mg ZFK tablet. Copyright (c) 2008 John Wiley & Sons, Ltd.
Chem Res Toxicol. 2008 Feb; 21(2): 374-85
Sun H, Yost GS
SPD-304 is a recently discovered small-molecule TNF-alpha antagonist. However, SPD-304 contains a potentially toxic 3-alkylindole moiety. Previous studies on 3-methylindole and the 3-alkylindole-containing drugs zafirlukast and MK-0524 structural analogues found that they were bioactivated by cytochrome P450s through a dehydrogenation process to form 3-methyleneindolenine intermediates that are electrophilic alpha,beta-unsaturated iminium species. These electrophiles could react with protein and/or DNA nucleophilic residues to cause toxicities. In the present study, we found that SPD-304 was bioactivated through a similar dehydrogenation mechanism to produce a similar electrophilic 3-methyleneindolenine intermediate. The electrophile was trapped with nucleophilic glutathione and identified by LC/MS/MS. The iminium or another reactive intermediate also was a mechanism-based inactivator of CYP3A4. The inactivation parameters were K I = 29 microM and k inact = 0.047 min (-1). In addition, SPD-304 was metabolized through hydroxylation, N-dealkylation, and epoxidation pathways, and several metabolites and glutathione adducts were characterized by tandem mass spectrometry. The metabolism profile was also evaluated by in silico molecular docking of SPD-304 into the active site of CYP3A4, which predicted that the dehydrogenation reaction was initiated by 3-methylene C-H atom abstraction at the trifluoromethylphenyl-1 H-indol-3-ylmethyl portion of SPD-304. Hydroxylation of the 6'-methyl of the dimethylchromone portion of SPD-304 was the other major predicted metabolic pathway. The molecular models correlated precisely with experimental metabolic results. In summary, dehydrogenation of SPD-304 may cause toxicities through the formation of electrophilic intermediates and cause drug-drug interactions through CYP3A4 inactivation.
[Adverse effects of leukotriene-antagonists]
Nippon Rinsho. 2007 Oct 28; 65 Suppl 8: 272-6
Chohnabayashi N, Sugiura R, Nishimura N
Tolerability of leukotriene modifiers in asthma: a review of clinical experience.
BioDrugs. 1999 Jun; 11(6): 385-94
Gozalo Reques F, Estrada Rodriguez JL
The so called leukotriene antagonists or, more accurately, the leukotriene modifiers are a rather heterogeneous set of drugs that work by several mechanisms. Such mechanisms include: (i) 5-lipoxygenase enzyme inhibition (e.g. zileuton); (ii) 5-lipoxygenase-activating-protein inhibition (e.g. quiflapon, BAYx 1005); (iii) LTD4-receptor antagonism (e.g. zafirlukast, montelukast, MK-571, pranlukast). The first leukotriene modifiers tested (L-649,923 and tomelukast) had adverse gastrointestinal effects. Since then, several leukotriene modifiers have been marketed, including zafirlukast, zileuton and montelukast. Zafirlukast has been associated with 8 cases of Churg-Strauss syndrome, although these were probably not caused by zafirlukast. It is more likely that this syndrome is related to the underlying illness, which was masked by corticosteroids, and revealed after zafirlukast-mediated asthma treatment allowed steroid withdrawal and unmasking of underlying vasculitis. The main adverse effects of zileuton include liver function test abnormalities, while montelukast, the most recently marketed, has so far shown minimal adverse effects. Zafirlukast causes a decrease in warfarin clearance and a clinically significant increase in prothrombin time, probably by cytochrome P450 isoenzyme interactions. Moreover, terfenadine decreases zafirlukast maximum serum concentrations. Calcium antagonists, cyclosporin, cisapride and astemizole are metabolised via the cytochrome P450 system, and interactions with leukotriene modifiers can be expected.
Comparison of antileukotrienes and antihistamines in the treatment of allergic rhinitis.
Am J Rhinol. 2007 Jul-Aug; 21(4): 439-43
Ho CY, Tan CT
BACKGROUND: The aim of this study was to compare the effect of antileukotriene (anti-LT), antihistamine, and a combination of anti-LT and antihistamine on the symptoms and nasal resistance in allergic rhinitis patients. METHODS: We performed a placebo-controlled study, with 120 persistent, moderate to severe allergic rhinitis patients randomly selected to receive the different treatments for 4 weeks: no treatment, 10 mg of cetirizine once per day, 20 mg of zafirlukast once per day, 20 mg of cafirlukast twice per day, a combination of 20 mg of zafirlukast and 10 mg of cetirizine once per day, or a combination of 20 mg of zafirlukast twice per day and 10 mg cetirizine once per day. The nasal secretion nitric oxide (NO) concentration, nasal symptom score, and nasal resistance were measured before and after treatment. RESULTS: Total symptom scores improved in each treated group compared with the control group (p < 0.05). Nasal obstruction significantly improved in the anti-LT-treated groups (p < 0.05). High-dose anti-LT or the combination of low-dose anti-LT and antihistamine significantly improved allergy symptoms compared with no treatment, low-dose anti-LT, or antihistamine alone (p < 0.05). Furthermore, anti-LT decreased NO concentration in nasal secretions (p < 0.05), regardless of the dose administered. CONCLUSION: These results suggest that high-dose anti-LT alone or the combination of low-dose anti-LY and antihistamine can effectively treat allergic rhinitis.
Effects of zafirlukast on capsular contracture: controlled study measuring the mammary compliance.
Int J Immunopathol Pharmacol. 2007 Jul-Sep; 20(3): 577-84
Scuderi N, Mazzocchi M, Rubino C
Capsular contracture is a highly distressing, difficult complication after breast augmentation for both the patient and the surgeon. Although capsular contracture is a multifactorial process, one common denominator in the successful treatment of this complication is believed to be the abatement of inflammation. Leukotriene antagonists have recently emerged as effective prophylactic agents in reactive airway diseases. Anecdotal reports have indicated that zafirlukast (Accolate, AstraZeneca) effectively reverses capsular contracture. A prospective study of capsular contracture in 120 female patients in whom a total of 216 prostheses were implanted was performed. The hardness of capsular contracture was assessed by means of the mammary compliance method (Anton Paar Mammacompliance system). The patients were divided into two groups: patients in group A received zafirlukast for a 6-month period, while those in group B received vitamin E. The results show a significant decrease of the values of breast compliance after 6 months in group A but not in group B and that the variation in compliance after 6 months in group A compared to group B is statistically significant. In zafirlukast-treated patients, we observed a reduction in mammary compliance of 7.69 percent after 1 month, 16.78 percent after 3 months and 24.01 percent after 6 months. The present study suggests that zafirlukast may be effective in reducing pain and breast capsule distortion in patients with longstanding contracture who are either not surgical candidates or who do not wish to undergo surgery.
Aesthetic Plast Surg. 2008 Jan; 32(1): 179-80
Grella E, Grella R, D'Andrea F